Depression is a debilitating disease causing significant mortality and affecting up to ten percent of the population. Selective serotonin reuptake inhibitors (SSRI's) have proven to be effective in treating depression, but have the disadvantages of delayed onset of antidepressant activity, limited efficacy and significant side effects. See Novel strategies for pharmacotherapy of depression, K. A. Maubach, N. M. J. Rupniak, M. S. Kramer, and R. G. Hill, Current Opinion in Chemical Biology 1999, 3, 491–499. Another class of clinically effective antidepressants are substance P (SP) antagonists which show high affinity and selectivity for the neurokinin 1 (NK-1) receptor. Robust antidepressant activity has been reported for two NK-1 antagonists, MK-869 (M. S. Kramer, et al., Science 1998, 281 1640) and CP-122,721 (T. J. Rosen, et al., Bioorganic and Medicinal Chemistry Letters 1998, 8, 28 and CNS Drug News, December, 2000, 24). NK1 antagonists offer an alternative approach for treating depression in patients that respond poorly to the SSRI's and other available drugs.
The first dual NK-1 antagonists-serotonin reuptake inhibitors were described by Ryckmans et al. [Bioorganic and Medicinal Chemistry Letters 2002, 12, 261–264]. Ryckmans discloses phenoxy acetamides and phenyl propionamides as NK-1 antagonists and serotonin reuptake inhibitors and the potential of a new generation of antidepressants.
U.S. Pat. No. 6,136,824 discloses piperidinyl-propane-2-derivatives which exhibit both NK-1 receptor antagonism and/or selective serotonin reuptake inhibitor (hereinafter referred to as SSRI) activity.
International Application WO2004/005256 discloses cyclic amine derivatives that exhibit both NK-1 receptor antagonism and/or SSRI activity.
International Application WO2004/005255 discloses N-benzyl-3-phenyl-3-heterocyclic-propionamide compounds as tachykinin and/or serotonin reuptake inhibitors.
The compounds of the present disclosure have activity as NK-1 antagonists and/or also have activity as selective serotonin reuptake inhibitors. Thus, they are of use in the treatment of conditions mediated by tachykinins and/or selective inhibition of the serotonin reuptake transporter protein. One aspect of the class of compounds of the present disclosure exhibit both NK-1 receptor antagonist and SSRI activity.
Thus, novel dual NK-1 antagonists and SSRI inhibitors effective for the treatment of numerous disorders, such as central nervous system disorders, would be advantageous.